Combination antiretroviral therapy for patients infected with HIV can reduce viral loads to extremely low levels. However, cessation of these therapies leads to viremia within weeks due to a persistent reservoir of latently infected cells. Instead of continuing to subject patients to a lifetime of antiretroviral therapy, it would be preferable to develop therapies that could purge the latent viral reservoir, thereby allowing patients to stop all medications. Many groups are actively pursuing this goal. Among the most clinically advanced approaches in this area is the use of histone deacetylase inhibitors (HDACi). In clinical trials where HIV infected patients on ART were treated with a single dose of an HDACi, HIV RNA production in T cells rapidly increased, but no increase in virus production was observed. The overall effect of this single intervention on the latent reservoir is therefore not known. We have recently discovered that cIAP1 antagonists, a class of Smac mimetics that are known activators of the non-canonical NF-?B signaling pathway, can also activate latent HIV in an experimental cell line. Furthermore, these compounds act synergistically with HDACi to reactivate latent HIV. This proposal is designed to follow up on these discoveries and to provide compounds for clinical reactivation of HIV in order to enable a complete cure of infection in these patients. Specifically, we will perform in vitro studies to identify the optimal combinations of clinical-stage Smac mimetics and HDACi in both a cell line model and in patient cells. In addition, in vitro analysis of absorption, metabolism and toxicity with be performed, and the potential for drug-drug interactions will be examined. We will improve the potency, efficacy and pharmacokinetic profile of a next-generation Smac mimetic and reduce any potential liabilities it may have. Optimized combinations of SMac mimetics and HDACi will be tested in a mouse model of HIV latency reactivation and the precise mechanisms involved in this reactivation will be identified.